Neurons exhibit <i>Lyz2</i> promoter activity in vivo: Implications for using LysM‐Cre mice in myeloid cell research

Orthgieß, Johannes; Gericke, Martin; Immig, Kerstin; Schulz, Angela; Hirrlinger, Johannes; Bechmann, Ingo; Eilers, Jens

doi:10.1002/eji.201546108

Cited by 88 publications

(74 citation statements)

References 21 publications

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“…5E). It is worth noting that neuronal expression of Cre recombinase in LysM Cre mice has been reported by various groups including ours (Clausen et al, 2016; Orthgiess et al, 2016). However, since TNFR2 is virtually absent in CNS neurons (Brambilla et al, 2011; Zhang et al, 2014), neuronal Cre activity should not affect TNFR2 expression in LysM Cre : Tnfrsf1b fl/fl mice.…”

Section: Resultssupporting

confidence: 59%

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

et al. 2017

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Summary In multiple sclerosis (MS), soluble tumor necrosis factor (TNF) is detrimental via activation of TNF receptor 1 (TNFR1), whereas transmembrane TNF is beneficial primarily by activating TNF receptor 2 (TNFR2). Here we investigate the role of TNFR2 in microglia and monocytes/macrophages in experimental autoimmune encephalomyelitis (EAE), a model of MS, by cell-specific gene targeting. We show that TNFR2 ablation in microglia leads to early onset of EAE with increased leukocyte infiltration, T cell activation, and demyelination in the central nervous system (CNS). Conversely, TNFR2 ablation in monocytes/macrophages results in EAE suppression with impaired peripheral T cell activation, and reduced CNS T cell infiltration and demyelination. Our work uncovers a dichotomy of function for TNFR2 in myeloid cells, with microglial TNFR2 providing protective signals to contain disease, and monocyte/macrophagic TNFR2 driving immune activation and EAE initiation. This must be taken into account when targeting TNFR2 for therapeutic purposes in neuroinflammatory diseases.

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Section: Resultssupporting

confidence: 59%

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

et al. 2017

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“…As always, each model has its limitations and particular intricacies the user needs be aware of for the design of the specific experimental set up and the question asked. The study of brain macrophages has been challenging, starting with the observation that the popular LysM Cre animals, that are often used for the study of peripheral myeloid cells, and were hence used to target microglia, show considerable rearrangements in neurons [33]. Here, we establish that also neither Cx 3 cr1 CreER nor Sall1 CreER transgenic mice specifically target microglia: Cx 3 cr1 CreER animals display in addition rearrangements in non-parenchymal CX 3 CR1 + CNS macrophages, while Sall1 CreER transgenic mice show prominent recombination in the neuro-ectodermal lineage.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of CreER transgenic mice for the study of brain macrophages: A case study

et al. 2019

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Conditional mutagenesis and fate mapping have contributed considerably to our understanding of physiology and pathology. Specifically, Cre recombinase‐based approaches allow the definition of cell type‐specific contributions to disease development and of inter‐cellular communication circuits in respective animal models. Here we compared Cx3cr1CreER and Sall1CreER transgenic mice and their use to decipher the brain macrophage compartment as a showcase to discuss recent technological advances. Specifically, we highlight the need to define the accuracy of Cre recombinase expression, as well as strengths and pitfalls of these particular systems that should be taken into consideration when applying these models.

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“…Wt mice that received Tgfbr2 Myeko bone marrow exhibited mortality (Figure 1E) and brain microhemorrhages (Online Figure IF) similar to Tgfbr2 Myeko mice. These data exclude the contribution of brain residing microglia 10,11 and other cell types reported to be targets of LysM-cre 12 . Together, these data suggest that deficiency of TGFβ signaling in myeloid cells leads to decreased lifespan due to spontaneous stroke.…”

Section: Resultsmentioning

confidence: 64%

Attenuation of Myeloid-Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

Hollander

Latour

Yang

et al. 2017

Circulation Research

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Rationale Cryptogenic strokes, those of unknown cause, have been estimated as high as 30–40% of strokes. Inflammation has been suggested as a critical etiological factor. However, there is lack of experimental evidence. Objective In this study, we investigated inflammation associated stroke etiology using a mouse model that developed spontaneous stroke due to myeloid deficiency of TGFβ signaling. Methods and Results We report that mice with deletion of Tgfbr2 in myeloid cells (Tgfbr2Myeko) developed cerebrovascular inflammation in the absence of significant pathology in other tissues, culminating in stroke and severe neurological deficits with 100% penetrance. The stroke phenotype can be transferred to syngeneic wild type mice via Tgfbr2Myeko bone marrow transplant, and can be rescued in Tgfbr2Myeko mice with wild-type bone marrow. The underlying mechanisms involved an increased type 1 inflammation, and cerebral endotheliopathy, characterized by elevated NFκB activation and TNF production by myeloid cells. A high fat diet accelerated stroke incidence. Anti-TNF treatment, as well as metformin and methotrexate, which are associated with decreased stroke risk in population studies, delayed stroke occurrence. Conclusions Our studies show that TGFβ signaling in myeloid cells is required for maintenance of vascular health, and provide insight into inflammation-mediated cerebrovascular disease and stroke.

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Neurons exhibit Lyz2 promoter activity in vivo: Implications for using LysM‐Cre mice in myeloid cell research

Cited by 88 publications

References 21 publications

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Opposing Functions of Microglial and Macrophagic TNFR2 in the Pathogenesis of Experimental Autoimmune Encephalomyelitis

Comparative analysis of CreER transgenic mice for the study of brain macrophages: A case study

Attenuation of Myeloid-Specific TGFβ Signaling Induces Inflammatory Cerebrovascular Disease and Stroke

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